The major emphasis of this project was the study of SIV pathogenesis in experimentally- infected macaques with the intent of dissecting factors which contribute to biologic variability in disease course. Using quantitative competitive PCR (QC-PCR) for plasma viral RNA, tree distinct patterns of viral replication were observed to be associated with different disease courses in SIVsm-infected macaques. Persistent high viremia was characteristic of animals that progressed to AIDS; in contrast, low levels of primary viremia with sustained control of virus levels was observed in nonprogressors. Two molecular clones have been the focus of ongoing SIV pathogenesis studies, SIVagm9063-2 originating from an African green monkey and SIVsmE543-3, originating from a sooty mangabey monkey. Both these cloned viruses induce immunodeficiency in pig-tailed macaques. In contrast, African green monkeys (AGM) remain healthy following experimental infection with SIVagm9063-2, making this virus system a relevant model for species-specific virulence. The dynamics of viremia in macaques and AGM infected with SIVagm differ substantially; macaques exhibit a massive burst of acute viremia followed by down regulation, the extent of which appears to correlate inversely with the rate of disease onset. A slower onset of viremia was observed in AGM and peak levels were 100 to 1000-fold lower than those observed in infected macaques at any time during infection. Infected AGM maintained a low level of continued viral replication as evidenced by evolution of viral genotypes in the blood and persistent plasma viremia. The SIVsmE543 clone, in contrast, is a relevant model for intra-species variability in disease progression in pig-tailed macaques. This cloned virus is tropic for both lymphocytes and macrophages, is difficult to neutralize in vitro (reminiscent of primary HIV-1 isolates) and induces rapid progression without an SIV-specific antibody response in 50% of inoculated macaques. This virus provides an excellent opportunity to dissect the determinants of neutralization of SIV strains as well as providing a model to study the pathogenesis of rapid progression.